http://faculty.washington.edu/ely/JOM3.html
The Journal of Orthomolecular Medicine. 1998; 13(2):
105-109.
Hemorrhagic Stroke in Human Pretreated with Coenzyme Q10:
Exceptional Recovery as Seen in Animal Models
John T.A.Ely,Ph.D.(1); H.Hugh Fudenberg, M.D.(2); Emile G.
Bliznakov,M.D.(3); John D.Branch,D.O.(4) .
1)Radiation Studies Box 351650,
University of Washington, Seattle, WA 98195
2)NeuroImmuno Therapeutics
Research Foundation, 1092 Boiling Springs Rd, Spartanburg, SC 29303
3)
Biomedical Research Consultants, 2801 N. Course Drive (H-205), Pompano Beach, FL
33069
4)Department of Family Practice, Western University of Health Sciences,
Pomona, CA
Abstract
Minimizing neurologic
injury from stroke is still the elusive goal of large scale controlled clinical
trials of new synthetic agents whose efficacy is dependent upon prompt
post-insult administration. In 26 years of animal model stroke studies, one
substance that afforded a markedly higher degree of protection than all others
tested was a normal endogenous molecule, coenzyme Q10 (Q10). Because of
increasing worldwide use of Q10, we are able serendipidously to report on
possibly the first observation of a human recovering almost completely from an
unexpected cerebral hemorrhage following four weeks of pretreatment with Q10 at
a pharmacologic dose commonly employed for a wide variety of disorders. Clearly,
clinical studies are needed to confirm the significance of our observed result.
These would be facilitated by the safety and efficacy of Q10 already proven in
nine large scale international trials in cardiomyopathy, etc., and its apparent
benefits in numerous disorders, including AIDS and possibly aging itself.
However, the confirmation should be done in trials specifically designed for
stroke because of detection difficulty arising from the anticipated protection.
If confirmed, this result does not diminish the urgent need for development of
synthetic stroke agents, but may facilitate their realization by decreasing the
protective functions needed from the agents.
_____________________________________________
Abbreviations: coenzyme
Q10, Q10; cardiovascular diseases, cvd
Introduction
Ischemic
reperfusion injury (IRI) in various organs, especially brain, heart and kidney
has recently been cited as responsible for the majority of deaths in developed
countries (1). Annual US stroke specifics include 150,000 deaths, and only circa
one third of the 400,000 survivors have little or no impairment (2). We report
an unexpected favorable recovery from a complicated cerebral hemorrhage that is
consistent with the remarkable results obtained for animal models of stroke
using coenzyme Q10, reported to be far superior to all other substances tested
(3,4). Gerbil survival to 40 days following carotid ligation induction of
ischemic stroke, was 45% on Q10, over twice the 20% on naloxone, the second best
agent tested (no deaths occurred after day 4 and the experiments were terminated
at day 40). Such recoveries are not implausible since Q10's exceptional
antioxidant and free radical quenching properties have been cited as offering
"great implications in the treatment of IRI"(5).
The first isolation of
Q10 was from beef heart mitochondria by Frederick Crane et al at Wisconsin in
1957. After determination of the molecular structure and synthesis of Q10 by
Karl Folkers and his coworkers at Merck in 1958, its successful use in
cardiovascular diseases and a steadily growing list of other conditions that now
include cancer, AIDS, aging etc., in humans and animals have been reported
(5-12). It has been shown to be safe and efficacious in nine large scale
international trials, and has no known toxicity or side effects (5). At least
three functions have been demonstrated for Q10 and it must be continually
replaced throughout life (5); it is necessary for: bioenergetics in the
mitochondria; stability of mitochondrial and other cellular membranes; and
important antioxidant roles in many tissues (including stronger protection of
LDL against oxidation than is provided by vitamin E). Endogenous synthesis of
Q10 uses a complex and easily imperiled process requiring many vitamins and
other nutrients as substrate. Low levels of Q10 in blood and other tissues have
been associated with cardiovascular diseases, cancer and other disorders. Such
Q10 deficiency states may result from at least three factors: increased
utilization, reduced endogenous synthesis and inadequate dietary intake (5).
Oral supplementation of Q10 between 100 and 400 mg/d has been reported to
produce significant dose-dependent enhancement of recovery in these patients
(5). Such amounts of Q10 are unlikely to be provided by dietary intake only
(10).
Patients and Methods
We have been engaged in a program
designed to accelerate evaluation of the remarkable efficacy reported in recent
years for Q10 in animal and human studies of a wide variety of disorders
including cvd, neurological, immunological, etc. We have posted a Q10 update on
a University of Washington web site (5) and urged physicians everywhere to
consider its relevance to their practices. Incidental to this routine study of
symptom and Q10 blood level response in many patients of numerous physicians, we
were able to recognize, analyze, and report this surprising recovery from an
unanticipated stroke due to accidental trauma in one patient.
Stroke
Patient Pretreated with Coenzyme Q10
The patient was a 69 year old
Caucasian female with marked short term memory deficit associated with recent
onset diabetes, poorly controlled by diet. She had entered the care of a local
physician (without complete medical records) and elected to supplement Q10
(Nutricom Products, PO Box 3345, Saratoga, CA 95070), 400 mg chewed with circa 5
grams of fat (to enhance absorption) at one meal each day. In our view, her age
and diet made it likely that a Q10 deficiency state existed (5). After four
weeks of supplementation she suffered bifrontal cerebral hemorrhage due to a
fall on pavement. That trauma resolved quickly and she was released. Two weeks
later she was again brought to the hospital in coma following syncope in her
residence with (suspected) head trauma. Vitals: T: 99.7, P: 110, R: 18. BP:
136/74.
Her temperature peaked at 102.2 one hour subsequent to
presentation. Basilar crackles were heard in the left lung field and a 3/6
systolic murmur was noted at the left sternal border. Her abdomen was nontender
and her neurologic examination revealed the absence of deep tendon reflexes.
Corneal reflexes were not intact. The patient was unresponsive even to pain. Her
white blood count was 12,500 with 92% lymphocytes. Her serum glucose level was
619 and her serum beta oxybutyrate was 13.4. A chest x-ray showed a left lower
lobe infiltrate. Her urine culture was positive for both Candida albicans and
Group D enterococci. A CT scan of the head was performed and showed resolution
of a bifrontal hemorrhage which had been noted after her previous fall.
Encephalomalacia was noted in the area of a prior right temporal lobe
hemorrhage, and a small epidural hemorrhage was seen in that region, as
well.
During the course of her hospitalization, the patient was treated
using an insulin drip, then graduated to sliding scale insulin. A lumbar
puncture was performed and was unremarkable; CSF cultures were negative.
Seizures which had been noted at the time of admission were controlled using
Dilantin. Intravenous antibiotics were used to treat the pneumonia and urinary
tract infections. Gradually, the patient's level of consciousness returned to
normal. A right-sided hemiparesis was then evident. This resolved over the next
few days. She was oriented to name and place at the time of discharge but could
not identify the year or the president. She was able to feed herself and was
eating 100% of her meals prior to discharge. On her tenth hospital day, she was
found to be afebrile and euglycemic and was discharged to a skilled nursing
facility on antibiotics, anticonvulsants and insulin.
In the course of an
examination two days subsequent to discharge, the patient was found to be alert
and talkative. She was still unable to name the president, but quite capable of
discussing events from the distant past identifying common objects and
ambulating without difficulty. Her short-term memory was still very poor. No
motor or sensory deficit was noted.
Discussion
Of principal
interest, as stated above, is the fact that for several weeks prior to her
initial fall and hospitalization discussed here, the patient had been taking
coenzyme Q10, 400 mg daily at one meal with ca 5 g of fat (i.e. peanut butter)
to enhance absorption. Despite sustaining numerous significant insults in close
temporal proximity, including a bifrontal cerebral hemorrhage, an epidural
hemorrhage, diabetic ketoacidosis and pneumonia with its attendant hypoxemia,
this patient was able to return to her premorbid state with no neurologic
sequelae.
Pre- and Post-stroke Q10
A neuroprotective effect of
coenzyme Q10 given both pre- and post-stroke has been demonstrated by studies in
three animal models and reported in the literature (3,4). The central question
of this paper relates to the relevance of those animal results to humans. A
variety of animal experiments using Q10 by Bliznakov, Folkers and others (11,13)
on immunity and various organ functions have been shown to predict and or
duplicate the corresponding effects in humans. Therefore, in view of the number
of effects that have been shown to occur in both humans and lower mammalian
species, it should not be surprising if the stroke protection reported here
proves real. Hence, we suggest that clinicians should inquire if Q10
pretreatment had occurred in those rare cases where recovery from stroke seems
far better than appeared possible during the acute phase. In addition, since:
[1] the gerbils were treated successfully with Q10 four hours after induction of
stroke; and [2] no side effects have been observed in humans from Q10 in large
numbers of clinical trials (5), prompt post stroke administration of Q10 in
humans seems indicated. Kandela recently reported a six-hour post-stroke
therapeutic window exists in humans also (14). What harm to put Q10 in hospital
formularies?
Reduction of Stroke Incidence
Decreasing
incidence is also clearly vital to reducing stroke morbidity and mortality. In
spite of the exceptional protection that may prove to result from coenzyme Q10
(and stroke drugs in development), the physician faces the task of identifying
and reducing several classes of stroke risk in essentially all people consuming
the developed nations' diets. These individuals will have varying degrees of
arteriosclerosis and other lesions due to elevated levels of xanthurenic acid
and homocysteine intermittent or persistent since childhood. To reduce the
incidence, we suggest physicians must educate the public in simple modalities
that utilize certain inexpensive substances (notably pyridoxine, other B
vitamins, magnesium and trivalent Cr) , previously demonstrated in animal and
human studies to prevent vascular disease including stroke. Those studies by
Kotake, Ellis, McCully, Mertz, etc., and the methods, published and known for
some decades (since Karl Folkers and his coworkers determined the structure and
function of pyridoxine), have recently been reviewed (15).
Additional
reasons for large scale supplementation beyond middle age
In addition to
protection against stroke, the findings of numerous scientific studies mandate
supplementation of Q10 by all humans past middle age to optimize quality of life
and minimize cost of health care (5,7). These include the critical dependence of
Q10 synthesis upon diet, its decline after age 20, and the acceleration of all
types of disease risk and aging changes associated with that decline (5). It is
of great importance to note that: human brain Q10 concentration at age 80 is
decreased to roughly half the value at age 40 (7) In both animal and human
investigations, diseases of every body system are increased when Q10 deficiency
states afflict those systems (5). In very old mice (aged 16 to 18 months) (11)
Q10 has been reported to reverse the immune senescence associated with thymic
involution, restoring youthful immune response and resistance to infections and
neoplasia (9, 12). The same studies reported that aging itself was markedly
slowed in terms of the Q10-treated animals' appearance and agility, and their
mean survival time after treatment was 56 % longer than in controls, 218 vs 140
days; the ages at death were ca 104 weeks for the last control mouse and ca 150
weeks for the last treated mouse (11,13). From human clinical trials in
cardiology, cancer and infectious disease alone it appears that significant
improvements in health and major decreases in cost of health care are associated
with Q10 supplementation (5). The rationale for Q10 in AIDS and a striking
clinical response in human AIDS patients treated with Q10 have been reported by
Folkers, Langsjoen, et al (5,16).
Recommendations to the clinical
community
Hence, oral supplementation of Q10 to compensate for age
impaired synthesis and inadequate food content should provide many clinically
established benefits. In addition to these, if the present paper does truly
reflect a human equivalence of the impressive animal stroke model findings,
widespread Q10 intake by those above middle age can produce a marked reduction
in the incidence and severity of stroke. These results suggest it is urgent that
the need for coenzyme Q10 supplementation be evaluated for people above middle
age, and especially for those considered at risk for cardiovascular disease
including stroke. At the present time, far less than 1 % of the US population
may be supplementing Q10 at or above the 100 mg/day level. Three major reasons
for this are: high cost; lack of physician exposure to information; and dearth
of clinical laboratories that offer the Q10 blood test at a low cost (ca US$50).
Solutions to these three obstacles may be at hand: [1] The retail cost of a 100
mg chewable Q10 tablet emulsified with lecithin has recently been reduced 62% by
one California company; hopefully, increased use will result in lower costs from
Japan for all distributors; [2] A physician's update written by Langsjoen is
available on the web (5); and [3] With that update, there is an extremely brief
electronic questionnaire to assess demand for the blood-test as a function of
price. If demand is sufficiently high, clinical labs at the University of
Washington hope to automate the research assay (provided to us by Folkers) and
be able to offer a low cost test to facilitate the clinical evaluation of Q10
supplementation in every medical specialty. Meanwhile, all physicians could
benefit from 40 years of clinical experience by the well-known Canadian
investigator, Wilfrid E. Shute, MD, using vitamin antioxidants in cardiovascular
disease and stroke in the "early days" before Q10
(17).
Acknowledgments
Extensive involvement in the analysis
and writing was provided by all four authors including Hugh Fudenberg,
immunologist and investigator of diverse neurologic injuries, and Emile
Bliznakov, human and animal model Q10 researcher. John Branch is one of the
physicians who performed definitive examinations on the patient and into whose
care she was released, and under whose observation she remains. Support is
acknowledged by one of us (JE) from the Wallace Genetic Foundation and the
Northwest Oncology Foundation; and by another (HHF) from NeuroImmuno
Therapeutics Research Fn. We thank Cheryl A. Krone, PhD, of NOAA and Alena
Langsjoen, MS, for editorial assistance, and Peter H. Langsjoen, MD, for helpful
comments.
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